Preparation of certain triazoles



United States Patent 3,183,241 PREPARATION OF CERTAIN TRIAZOLES Phyllis D. Oja, San Francisco, Calif., assignor to The Dow Chemical Company, Midland, Mich, a corporation of Delaware No Drawing, Filed Feb. 1'1, 1963, Ser. No. 258,666 4 Claims. (Cl. 260-608) H N-NHii i l-Y where Y is a substituent member selected from the group consisting of hydroxyl (OH), mercapto (SH), amino (NH and hydrazino (NHNH These compounds exhibit useful antimicrobial action in standard tests therefor.

Heretofore, 5-substituted-4-amino-3-hydrazinotriazoles have been prepared only with great difficulty and in very small yields. There has been no generally applicable method for preparing these compounds although certain members havebeen prepared by a variety of different methods each of which is useful for a given specie. To illustrate, 4-amino-3,S-dihydrrzinotriazole has been reportedto have been prepared from the reaction of dicyandiamide and hydrazine [Stoll and Krauch, J. Prakt. Chem., 88, 306 (1913)], or by the reaction of hydrazine salts and guanidine [Stoll and Bowles, Ber 41, 1101 (1908)].

The preparation of 5-mercapto-4-amino-3hydrazinotriazole has been reported from the reaction of a variety of sulfur compounds with hydrazine, but yields have been low and the product has been contaminated by many other reaction products. J. Chem. Soc., 1952, 481140; Audrieth et al., J. Org. Chem., 19, 733 ii, and Stoll and Bowles, Ben, 41, 1101 (1908).

It is a principal object of the present invention to pro vide a novel process for preparing certain S-substituted- 4-amino-3-hydrazinotriazoles which is generally applicable. I

It is another object of the present invention to provide a process for preparing these compounds in markedly higher yields than by traditional processes. 7

It is an additional object of the present invention to provide a new process for controllably and smoothly preparing these particularly hydrazinotriazoles without the coproduction of undesirably large amounts of contaminating byproducts.

It is still a further object of the present invention to prepare certain novel 5substituted-Famine-3 hydrazino triazoles.

These and other objects and advantages readily will become apparent from the detailed description presented hereinafter.

: In accordance with the present invention triaminoguanidine in free base formis dissolved or'dispersecl in an inert, polar organic medium and reacted at a temperature of from about 100 to about 155 C., ordinarily from See, for example, Hoggarth,

about 110 to about 150 C., from about 0.5 to about 12 hours or more with a compound of the structure R2 wherein Z is a member selected from the group consisting of oxygen (=0), sulfur (=S, imino (=NH) and hydrazono (=NNH and, R and R are members independently selected from the group consisting of amino (NH hydrazine (NHNH and methyl mercapto (SCH and further characterized that if Z is a member selected from the group consisting of :NH and =NNH one of the groups, R and R must also be a member selected from the group consisting of NH;, and --NHNH The general reaction may be represented by the following equation:

rnNNHoNHNHz R1-C-Rz NH, l

Ordinarily about stoichiometric amounts of reactants are employed, although the desired product can be recovered in somewhat reduced yields at other reactant ratios.

The amount of solvent to be employed is not limiting or critical except that it be such that the least soluble reactant is at least partially dissolved in the solvent at the reaction temperatures, and, that the reaction mixture be sufiiciently fluid to permit elficient agitation and heat transfer. Conveniently the weight ratio of solvent to reactants can range fromabout 1 to about 6 or more.

The reaction ordinarily is carried out at atmospheric pressure employing a solvent for the reactants which has a normal boiling point at least that of the operating temperature. However, if desired, elevated pressures can be employed. Under these latter conditions, solvents having a normal boilingpoint lower than the predetermined reaction temperature, i.e., from about 110 to about 130 C., can be used.

at temperatures much below about C. there is substantially no reaction. At temperatures above 155 C; there is detrimental loss ofvthe triaminoguanidine reactant from decomposition and polymerization reactions. Preferably the reaction temperature does not exceed about 150 C. Ordinarily the reaction is carried out at from about to about 150 C. Desirably, the process is carried out over 'a temperature range of from about about to about C.

The reaction time is not critical except that the process is continued for a suflicient period such that a predetermined yield of product is obtained. In general, im-

"proved yields are obtained as the reaction time is extended up to about 10 hours or'more. Ordinarily, reaction periods of from about 0.5 to about 12 hours, and preferably from about 4 to about 10 hours are employed.

The triaminoguanidine reactant readily'is prepared in accordance with the process set forth in a 'copending application of PpD; Oja and G. E. Hartzell, Serial No. 6059, filed February 1, 1960; In this process triaminoguanidine is produced by contacting an aqueous solution of a salt of triaminoguanidine with 'a'strongly basic quaternary ammonium anion exchange resin in basic'fonn. The resulting aqueous solution of free triaminoguanidine is concentrated and contactedwith an organic solvent which is nonreactive with triaminoguanidine and is a sol- The temperature range of operation is critical in that vent for water. The triaminoguanidine is crystallized from the resulting mixture and dried.

The R R C=Z reactant can be selected from a variety of available organic compounds, this choice being based on the predetermined 5-substituted-4-amino-3hydrazinetriazole product to be prepared. Dimethyltrithiocarbonate, S,S"-dimethyl dithiocarbonate, triaminoguanidine itself, guanidine, sym.-diaminoguanidine and urea are examples of suitable R R C:Z reactants of the classdeiined hereinbefore.

Solvents suitable for use in preparing the homogeneous reaction solution employed in the instant process are selected from the polar organic materials having a sufliciently high boiling point for use at a predetermined reaction temperature and pressure. Conveniently a solvent is selected which boils within the reaction temperature range in order to take advantage of the natural ebullution accompanying this phase change. However, this is not critical since solvents boiling above the reaction temperature range can be used. Also, at elevated pressures, solvents having a normal boiling point lower than the reaction temperature range can be used in the present process. Toluene, xylene, dimethylformamide, ethylene glycol and propylene glycol have been found to be particularly suitable solvents for use at atmospheric pressure.

Dimethylformamide is a very satifactory solvent. In those instances in which this solvent is reactive with amine by-products, no difiiculty is encountered in isolation of the desired product. Ethylene glycol has been found to be particularly suitable for use in preparing 4 amino 3,5 dihydrazinotriazole. This latter solvent however is not used with reactions employing thioesters because of its known reactivity with such materials.

The following examples will serve to illustrate further the present invention but are not meant to limit it thereto.

EXAMPLE 1 Preparation of 4-amino-3,5-dihydrazin0-I,2,4 (4H) triazole To about 400 milliliters of ethylene glycol were added at room temperature about 100 grams (0.96 gram mole) of triaminoguanidine. The resulting dispersion was heated at about 123125 C. for about 7.5 hours during which time the theoretical quantity of hydrazine was formed in the reaction mixture. Following the reaction period, the product mixture was cooled and isopropanol added to the solution to aid in the precipitation of the white crystalline 4-amino-3,S-dihydrazinotriazole product.

The identity of the crude 4-amino-3,S-dihydrazinotriazole was confirmed by its melting point of 191-196 C., and by infrared spectroscopy.

Infrared absorption peaks of this material (in a Nujol mull) were: 3.0, 3.05, 6.2, 6.45, 6.7 (weak), 8.0, 8.45, 8.7, 9.25, 9.68, 10.3 (broad), 10.75, 12.0 (broad, weak), 14.35 (very weak), and 14.75 (very weak) microns. Elemental analyses of a typical product were as follows:

Calculated Found for CzHgNg (Product Analyses) 0, percent 16. 68 16. 81 H, percent 5. 59 5. 64 N, percent 77.80 77. 92

Found: C, 11.09%; H, 4.64%; N, 51.74%; Cl, 32.45%. Calcd for C H N -2HCl: C, 11.0%; H, 4.6%; N, 51.8%; C1, 32.7%.

The free base compound was tested for biological activity in a standard soluble oil preservative evaluation test.

In this test, a cutting oil (Dromus B oil) is diluted 1:40 with tap water. A small amount of the compound to be tested is added with agitation to 285 cubic centimeters of the dilute oil in a 500 cubic centimeter Erlenmeyer flask. Fifteen cubic centimeters of spoiled oil inoculum is added. (Spoiled oil inoculum is an oil emulsion that has become contaminated because of bacterial action.) The flask and contents are then agitated at room temperature. Oil samples are taken at intervals over a 48 hour test period and these swabbed onto nutrient agar plates. If the oil has been preserved sterile (i.e. no bacterial growth forming on the nutrient plates) for 48 hours, two more 15 cubic centimeter aliquots of inoculum are added separatedly, one each at a 48 hour interval.

With the present compound, 250 parts per million of 4-amino-3,5-dihydrazino-1,2,4(4H)-triazole were found to kill the bacteria present from the three inoculations.

Initial screening tests for worm control were carried out with the hydrochloride salt to determine the eifective ness of the instant compound against pig ascarids and mouse tapeworm. For these tests, medicated diets containing about 0.12 percent of the dihydrochloride of 4- amino-3,5-dihydrazino-1,2,4(4H)-triazole were fed to mice naturally infected with tapeworms prior to inoculation with a standardized culture of Ascaris ova (roundworm of swine). Results of the screening showed this compound to be percent effective against these particular parasites.

EXAMPLE 2 Preparation of 4-amin0-3-hydrazino-S-hydr0xytriaz0le About 20.8 grams (0.2 gram mole) of triaminoguanidine was added with continual stirring at room temperature (about 25 C.) to about milliliters of dimethylformamide. About 24.4 grams (0.2 gram mole) of S,S'- dimethyl dithiocarbonate was added to the solution and the resulting reaction mixture gradually heated to the reflux temperature of about 116 C. Large amounts of methylmercaptan were evolved during this heating period.

The reaction mass was maintained at about 116 C. for one hour. Following this period, the product mixture was cooled whereupon about 21.9 grams of crude solid 5-hydroxy-4-amino-3-hydrazinotriazole product separated from the solution. This is equivalent to about a 84.3% yield. After recrystallization from water, the white, needle-like crystals were found to have an observed melting point of about 197-201 C. (with decomposition). Elemental analysis was as follows.

Found: C, 18.46%; H, 4.64%; N, 64.76%; 0, 12.14% (by diff). Calcd for C H N O: C, 18.40%; H, 4.6%; N, 64.85%; 0, 12.15% (by did).

A parachlorobenzaldehyde derivative was prepared by adding an excess of the aldehyde in methanol to an aqueous solution of the hydroxytriazole and heating, followed by neutralization with 10% aqueous sodium hy- 6 A hydrochloride salt of tlie 5-hydroxy-4-amino-3- I I claim:' hydrazinotriazole was prepared by dissolving a sample 1. A process for preparing 5-substituted-4-arnino-3- of the product in aqueous hydrochloric acid (6 N) and hydrazinotriazoles corresponding to the formula precipitating the salt by methanol addition.

The so-precipitated white .crystals were dried and 5 g )1 analyzed as follows: HQNNH Y I Calculated for Found z where Y is a member selected from the group consisting of -OH, -SH, NH and -NHNH which comprises;

2 8 21% mixing triaminoguanidine and a compound of the 51.232.3313: iii? i313 structure 0, percent (by difi.) 11. 6 16. 7 1

\C=Z A bright, yellow picrate derivative was prepared adding an ethanol solution of picric acid to an aqueous solution with a Polar Organic Solvent wherein Z in i of the hydroxy substituted amino hydrazinotriazole prodpound is a member selected from the group not. This compounds melted at about 191-1925 C. consisting of :0, =5, =NH and=NNH and, R (with decomposition) and analyzed as follows: and R are members independently selected from the group consisting of amino, hydrazine, and methyl calculated), Found mercapto and further characterized in that if Z is CSHPNQOE a member selected from the group consisting of :NH and -=NNH one of the groups R and R in Q Percent-u" said compound is a member selected from the group 11, percent 2. 5 2. 9

N, percent, 35,1 3 8 consisting of NH and NHNH and 0, percent (by did.) 35. 6 34. 0

heating said mixture at a temperature of from about 100 to about 155 C. [for a period of from about EXAMPLE 3 0.5 to about 12 hours.

30 2. A process for preparing 5-substituted-4-amino-3- hydrazinotriazoles corresponding to the formula Preparation of 4 -amino-3-hydrazz' no-S -mercapl0triazole Triaminoguanidine (about 20.8 grams; 0.2 gram mole) was suspended in about 100 milliliters dimethyl-form- HZNNHE i amide and about 27.7 grams dimet-hyl trithiocarbonate (0.2 mole) was added with stirring at room temperature. I

The resulting mixture was heated slowly to about 116 C. (reflux temperature) during which action considerable where Y is a member selected from the gPOllP consisting quantities of methylmercaptan were evolved. The reacof 2 and 2 which comprises; tion mass was maintained at reflux for about 4 hours mixing triaminogua and a compound Teacafter which time the solution was cooled to room tem- 40 Kant 0f the Structure perature. As the mass cooled, about 8.2 grams (28% R1 yield) of 5-mercapto-4-amino-3-hydrazinotriazole crystallized as pink needles therein. These were recrystallized from water and dried. The product was found to have a melting point of about 228.0-229.5 C. (with decom- Wlth a Polar Organic solvent Said Solvent. b.emg a position) and an elemental analysis as follows: member selected from the group conslstmg of toluene, xylene, dimethylformamide, ethylene glycol and propylene glycol, Z in said compound reactant agi??? Fmmd being a member selected from the group consisting of :0, =8, =NH, and =NNH and, R and R being members independently selected from the group C ercent 16. 45 16. 63

ligament-" 4.11 5.2% consisting of amino, hydrazrno and methyl mercapto N, percent- 57 50 Spment 0 2L9, R82 and further characterized in that if Z is a member selected from the group consisting of =NH and :NNH one of the groups R and R of said com- A benzaldehyde derivative was prepared following the pound is a member Selected f the group method described for Example 2. This derivative was sisting f and NHNH2, in the form of light grey needles WhlCh melted at 244-245 b) heating Said mixture at a temperature in the range (litemture Value of about to 150 C. for a period of from about Analysls gave: 69 4 to about 10 hours,

(c) cooling said mixture thereby to precipitate the Calculatedior Found corresponding 5-substituted-4-arnino-3-hydrazinotri- CmHwNflS azole product therein, and

(d) separating said product from the reaction mass. 5 5,32 2:32 21% 5 3. A process for preparing 4-amino-3,S-dihydrazino- N, percent- 25. 95 25.63 1,2,4(4H)-tr1azolewh1ch comprises; 7 s'percent 1M9 '(a) preparing a dispersion of triaminoguanidine in ethylene glycol, said dispersion having an ethylene Likewise triaminoguanidine can be admixed and reglycol-triaminoguanidine Weight ratio of about 4; fluxed in ethylene glycol with guanidine and with urea 7 (b) heating said dispersion at a temperature of about to give the corresponding 5-substituted triazoles. -l30 C. for about 8 hours,

Various modifications can be made in the present inven- (c) cooling the solution thereby formed to crystallize tion without departing from the spirit or scope thereof the 4-amino-3,S-dihydrazinotriazole product therein, for it is understood that I limit myself only as defined and in the appended claims.

(d) separating said product from the reaction mass.

3,183,241 7 8 4. A process for preparing 4-amino-3-hydrazino-5- References Cited by the Examiner hydroxy-triazole which comprises; UNITED STATES PATENTS (a) preparing a dispersion of triaminoguanidine and S,S'-dimethy1 dithiocarbonate in dimethylformamide, 7/44 DAleho 260-308 OTHER REFERENCES said dispersion containing about equal gram-mole 5 Stolle et al.: Ber. Deut. Chem., vol. 41, pages 1099- quantities of said triaminoguanidine and said S,S- dimethyldithiocarbonate, said dispersion having a dimethylformamide to triaminoguanidine and S,S- 1102 dimethyldithiocarbonate weight ratio of about 3, Brugerl Medlcmal chemlstfy York, PP- (b) refluxing said dispersion for about 1 hour, 10

(c) cooling the reaction product mixture thereby to precipitate the 4-amino-3 -hydrazino-5-hydroxytriazole product therein, and

(d) separating said product from the reaction mass.

IRVING MARCUS, Primary Examiner. NICHOLAS s. RIZZO, Examiner. 

1. A PROCESS FOR PREPARING 5-SUBSTITUTED-4-AMINO-3HYDRAZINOTRIAZOLES CORRESPONDING TO THE FORMUL 